Cystic Fibrosis
Cystic Fibrosis (CF) is a genetic, hereditary, autosomal recessive disease. The gene that causes the disease was first identified in 1989, and since then some 2000 different mutations have been discovered.
Under ordinary circumstances the CF gene enables production of a protein called Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), which provides a channel for chloride and bicarbonate ions. Generally, the CFTR channel regulates the flow of ions and water across cell membranes.
Mutations in the CF gene alter synthesis of the CFTR protein, which thus decreases in quantity or becomes non-functional. The CFTR channel is generally expressed in all epithelial tissue. This is why CF affects the sweat glands, making the sweat that they produce very salty. Since the mucous glands are also affected, CF alters the normally fluid consistency of mucus, making it thick and sticky. Organ systems protected by mucous glands can thus become congested (e.g., bronchi, pancreatic ducts, bile ducts).
In the lungs, this thickening of the mucus facilitates the arrival and persistence of germs termed “opportunistic pathogens” (e.g., Pseudomonas aeruginosa). The resulting process of infection/inflammation gradually leads to the destruction of the lung parenchyma, and thus to respiratory failure. In the pancreas, obstruction of the pancreatic ducts prevents enzymes from reaching the intestine, where they should facilitate nutrient absorption. In the liver, thick mucus can block the bile ducts, leading to liver disease.
CF patients may present with a variety of signs and symptoms, such as:
- Sweat with a high salt concentration
- Persistent cough
- Frequent lung infections
- Bronchospasm
- Poor growth
- Bulky, greasy stools
- Nasal polyposis
- Chronic sinusitis
- Male infertility
Diagnosis
The diagnosis of CF is a complex, multi-step process that includes:
- Neonatal screening (nationwide programme)
- Sweat testing
- Genetic analysis
Diagnosis is therefore generally made in the first few months of life. However, it sometimes occurs even in adult life, in the presence of genetic features with more nuanced clinical forms. In such cases, a CF specialist should oversee the testing that underpins diagnosis.
In Italy, there are 5800 patients diagnosed with CF (2020 data from the Italian CF Registry), while about one person in 30 is a “healthy carrier” of a CFTR gene mutation. Remember that, since CF is a recessive disease, both copies (alleles) of the gene that are present in the genome must be mutated for the condition to manifest itself.
Treatment
Chronic Treatments
Life-long treatment is essential, with a view to keeping the airways as mucus-free as possible. These consist mainly of:
- airway clearance techniques
- physical exercise
- appropriate nutrition
- drug treatments (mucolytics, hypertonic saline solution, aerosol antibiotics, azithromycin)
Treatment of infectious exacerbations
- intravenous antibiotic therapy
- steroids
Lung transplant
Some CF patients develop a severe form of the disease, leading to respiratory failure. In these cases, a lung transplant is a possible option.
Drugs modulating the genetic defect
For some years now, drugs have been available that can correct the genetic defect underlying the disease. The first of these drugs, which came onto the market in Italy in 2015, was Ivacaftor (Kalydeco®): defined as a CFTR protein enhancer, this drug can increase the target protein’s activity at cell membrane level. Ivacaptor is active on class III mutations of the CFTR gene – i.e., those mutations, present in about 5% of the Italian CF population, that limit the functioning of the CFTR channel on the cell membrane.
The most important advance in the efficacy of these modulators was the introduction of the latest drug (Kaftrio®), a triple combination therapy (two modulators and one enhancer). This has proved capable of substantially reducing respiratory symptoms, enhancing respiratory function in 70% of Italian CF patients. Kaftrio® became available for on-label use on 21 August 2020.
Current CF research is committed to identifying an efficacious therapy for patients with a genetic profile that makes current drugs unsuitable. The aim is to enable a significant change for the better in the lives of these patients, by developing a treatment that can successfully address their clinical needs.